Related Experiment Video
Updated: Apr 30, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Canagliflozin Promotes Structural and Functional Changes in Proximal Tubular Cell Mitochondria of
Mayra Trentin-Sonoda1,2, Yan Burelle2, Alex Gutsol2
1Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
Abstract:
The kidneys have a high-energy demand, relying on great rates of mitochondrial oxidative phosphorylation. Excessive glucose in the tubules leads to defective fatty acid oxidation, playing a key role in tubular injury and diabetic kidney disease progression. Besides its glucose-lowering action, canagliflozin (CANA) promotes kidney protective effects. We aimed to investigate whether the demonstrated kidney protective effects are extended to mitochondrial function and remodeling in proximal tubular cells from hypertensive-diabetic mice. Four weeks after streptozocin (STZ) induction of type 1 diabetes in genetic hypertensive (Lin) mice, they were fed either CANA-infused chow or a regular diet for 1 week. CANA treatment reverted the albuminuric state in LinSTZ mice. In PTECs from male mice, CANA promoted a complex mitochondrial network with less spherical and more branched organelles, with evidence of increased fusion. Those improvements reflected on the mitochondria bioenergetics, where CANA treatment induced an augmented baseline and maximum respiration rate, ATP production, and mitochondria membrane potential in PTECs, compared to LinSTZ. In females, CANA produced a milder response, increasing the mitochondrial network without affecting bioenergetics. In conclusion, in vivo CANA treatment positively affects proximal tubular cells' mitochondria in male hypertensive-diabetic mice with a minor impact in females. The improvement in mitochondrial function and structure might be key to the kidney-protective effects of CANA.
Insights
Canagliflozin (CANA) improves kidney mitochondria function and structure in male hypertensive-diabetic mice. This suggests that enhancing mitochondrial health may be crucial for CANA
Area of Science:
- Nephrology
- Mitochondrial Biology
- Diabetology
Background:
- Kidneys require significant energy via mitochondrial oxidative phosphorylation.
- Excess glucose impairs fatty acid oxidation, contributing to kidney injury and diabetic kidney disease.
- Canagliflozin (CANA) offers kidney protection beyond glucose lowering.
Purpose of the Study:
- To investigate if canagliflozin (CANA) improves mitochondrial function and structure in proximal tubular cells (PTECs) of hypertensive-diabetic mice.
- To assess the impact of CANA on kidney mitochondria in a mouse model of type 1 diabetes and hypertension.
Main Methods:
- Hypertensive mice (Lin) were induced with type 1 diabetes using streptozotocin (STZ).
- Diabetic hypertensive mice (LinSTZ) were treated with canagliflozin (CANA) or a control diet for one week.
- Mitochondrial structure and bioenergetics in PTECs were analyzed.
Main Results:
- CANA treatment reversed albuminuria in LinSTZ mice.
- In male PTECs, CANA promoted a more complex, fused mitochondrial network and enhanced bioenergetics (respiration, ATP production, membrane potential).
- In female PTECs, CANA increased mitochondrial network complexity but did not significantly alter bioenergetics.
Conclusions:
- In vivo canagliflozin treatment positively impacts proximal tubular cell mitochondria in male hypertensive-diabetic mice.
- Improvements in mitochondrial function and structure may underlie the kidney-protective effects of canagliflozin.
- The effects of canagliflozin on kidney mitochondria appear to be sex-specific.
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